Somatic mutations affect key pathways in lung adenocarcinoma.
Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
Ding
Li
L
The Genome Center at Washington University, Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63108, USA.
Getz
Gad
G
Wheeler
David A
DA
Mardis
Elaine R
ER
McLellan
Michael D
MD
Cibulskis
Kristian
K
Sougnez
Carrie
C
Greulich
Heidi
H
Muzny
Donna M
DM
Morgan
Margaret B
MB
Fulton
Lucinda
L
Fulton
Robert S
RS
Zhang
Qunyuan
Q
Wendl
Michael C
MC
Lawrence
Michael S
MS
Larson
David E
DE
Chen
Ken
K
Dooling
David J
DJ
Sabo
Aniko
A
Hawes
Alicia C
AC
Shen
Hua
H
Jhangiani
Shalini N
SN
Lewis
Lora R
LR
Hall
Otis
O
Zhu
Yiming
Y
Mathew
Tittu
T
Ren
Yanru
Y
Yao
Jiqiang
J
Scherer
Steven E
SE
Clerc
Kerstin
K
Metcalf
Ginger A
GA
Ng
Brian
B
Milosavljevic
Aleksandar
A
Gonzalez-Garay
Manuel L
ML
Osborne
John R
JR
Meyer
Rick
R
Shi
Xiaoqi
X
Tang
Yuzhu
Y
Koboldt
Daniel C
DC
Lin
Ling
L
Abbott
Rachel
R
Miner
Tracie L
TL
Pohl
Craig
C
Fewell
Ginger
G
Haipek
Carrie
C
Schmidt
Heather
H
Dunford-Shore
Brian H
BH
Kraja
Aldi
A
Crosby
Seth D
SD
Sawyer
Christopher S
CS
Vickery
Tammi
T
Sander
Sacha
S
Robinson
Jody
J
Winckler
Wendy
W
Baldwin
Jennifer
J
Chirieac
Lucian R
LR
Dutt
Amit
A
Fennell
Tim
T
Hanna
Megan
M
Johnson
Bruce E
BE
Onofrio
Robert C
RC
Thomas
Roman K
RK
Tonon
Giovanni
G
Weir
Barbara A
BA
Zhao
Xiaojun
X
Ziaugra
Liuda
L
Zody
Michael C
MC
Giordano
Thomas
T
Orringer
Mark B
MB
Roth
Jack A
JA
Spitz
Margaret R
MR
Wistuba
Ignacio I
II
Ozenberger
Bradley
B
Good
Peter J
PJ
Chang
Andrew C
AC
Beer
David G
DG
Watson
Mark A
MA
Ladanyi
Marc
M
Broderick
Stephen
S
Yoshizawa
Akihiko
A
Travis
William D
WD
Pao
William
W
Province
Michael A
MA
Weinstock
George M
GM
Varmus
Harold E
HE
Gabriel
Stacey B
SB
Lander
Eric S
ES
Gibbs
Richard A
RA
Meyerson
Matthew
M
Wilson
Richard K
RK
D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D011519:Proto-Oncogenes / Q000235:genetics